Topical pharmaceutical composition comprising a cholinergic agent or a calcium channel blocker

ABSTRACT

A method and composition are provided for the treatment of an anorectal disorder and for controlling the pain associated therewith. The method comprises administering to a subject in need of such treatment therapeutically effective amounts of a calcium channel blocker either alone or together with a nitric oxide donor. Amlodipine, anipamil, barnidipine, benidipine, bepridil, darodipine, diltiazem, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine, nicardipine, nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil and pharmaceutically acceptable salts thereof, are suitable calcium channel blockers.

[0001] This invention relates to the use of a calcium channel blocker ora cholinegic agent, particularly diltiazem and bethanechol, alone and incombination for the treatment of benign anal diseases where there is anassociated anal sphincter spasm. The invention particularly relates tothe treatment of anal fissures and painful haemorrhoidal conditions.

[0002] A fissure is a split in the skin of the distal anal canal. It isa common complaint in young adults with a roughly equal incidence inboth sexes. Acute fissures are very common and most heal spontaneously,but a proportion progress to form a chronic linear ulcer in the analcanal and show great reluctance to heal without intervention.

[0003] Treatment has remained largely unchanged for over 150 years andthe pathogenesis of anal fissure is not fully understood. The passage ofa hard stool bolus has traditionally been thought to cause anal fissure.Thus for acute fissures the avoidance of constipation, such as involvinga high bran diet, has been used as treatment for many years.

[0004] Anal dilators have also been involved in treatment. Typically adilator of medium size was coated with anaesthetic jelly and insertedinto the anal canal before the passage of stool to prevent exacerbationof the symptoms during defecation. The procedure was inconvenient andsuccess rate was low. The most common treatment, for chronic analfissures is a lateral internal sphincterotomy, which involves surgery tothe internal anal sphincter. This procedure, however, requireshospitalisation and leads in a sizeable number of patients to impairmentof continence (British Journal of Surgery 1996, 83, 1334-1344). As yetthere is no proven non-surgical treatment for chronic fissure, althoughlocal injection of botulinum A toxin shows early promise (Martindale,The Extra Pharmacopoeia 31st Edition p1516 and 1517).

[0005] A further potential non-surgical treatment that has recently beenreported for anal fissures and haemorrhoids is the topical use of anitric oxide donor, particularly glyceryl trinitrate. This reduces theinternal anal resting pressure (British Journal of Surgery, 1994, 81,1386-1389 and British Journal of Surgery, 1996, 83, 771-775 both bypresent inventors; Diseases of the Colon and Rectum, May 1995, p453-457,The New England Journal of Medicine Oct. 26, 1995, p1156 and 1157, WO95/32715 and its equivalent U.S. Pat. No. 5,504,117—all by Gorfine;British Journal of Surgery 1996, 83, 776-777).

[0006] At a meeting of the Royal Society of Medicine ColoproctologySession on Nov. 27, 1996, a paper entitled “The effect of alphaadrenoceptor blockade on the anal canal in patients with chronic analfissure” was presented showing that indoramin reduced maximum restingpressures in the anal canal after 1 hour by 35.8% in patients with analfissures. The author suggested a clinical trial to determine theefficacy of indoramin in the treatment of anal fissures.

[0007] In Dis Colon Rectum, February 1996, vol 2, no.2, p212-216nifedipine was reported as reducing the activity of the internal analsphincter in patients with high anal resting pressure, and was proposedfor use in relieving symptoms in patients with haemorrhoids or analfissures.

[0008] Haemorrhoids (‘piles’) are venous swellings of the tissues aroundthe anus. Those above the dentate line (the point where the modifiedskin of the outer anal canal becomes gut epithelium), which usuallyprotrude into the anal canal, are termed internal haemorrhoids, whilethose below this point are called external haemorrhoids. Due to internalpressure, internal haemorrhoids tend to congest, bleed and eventuallyprolapse; with external haemorrhoids painful thrombosis may develop.

[0009] Initial treatment of internal haemorrhoids involves a high-fibrediet and avoidance of straining at stool, so bulk laxatives and faecalsofteners may be indicated. Small bleeding haemorrhoids may be injectedwith a sclerosing agent such as oily phenol injection, or they may beligated with rubber bands. More severe and prolonged prolapse generallyrequires surgery. Surgical excision to remove the clot is used forthrombosed external haemorrhoids.

[0010] A range of mainly topical drug treatments is available forsymptomatic relief, but in many cases their value is a best unproven.Local anaesthetics may be included to relieve pain, and corticosteroidsmay be used when infection is not present. Preparations containingeither group of drugs are intended only for short-term use. Somepreparations include heparinoids and other agents frequently includedfor their soothing properties include various bismuth salts, zinc oxide,hamamelis, resorcinol and peru balsam.

[0011] In British Journal of Surgery 1994, 81, 946-954, Loder et alreviewed the possible pathology, pathophysiology and aetiology ofhaemorrhoids but came to no firm conclusions. The authors speculate thatthe anal cushions surround the anal canal act as a seal to prevent minorleakage from the anus and these cushions distend as a consequence ofhaemorrhoidal disease. The authors also explored whether haemorrhoids ismore prevalent in certain racial groups, whether it is a function ofdiet, habits or body habitus, whether it is a genetic disorder orwhether it is associated with other conditions such as hernia. No firmconclusions were, however, reached as to the aetiology of haemorrhoidsor how to treat it effectively.

[0012] Diltiazem is indicated orally for the treatment of anginapectoris and hypertension, and may be given intravenously in thetreatment of arterial fibrillation or flutter and paroxysmalsupraventricular tachycardia. Bethanechol is used as an alternative tocatheterisation in the treatment of urinary retention, gastric atony andretention, abdominal distension following surgery, congenital megacolon,and oesophageal reflux. It is given in doses of 5 mg subcutaneously or10 to 50 mg by mouth (Martindale, The Extra Pharmacopoeia, 31st Edition,p857 and p1417).

[0013] In a letter to the Lancet Jun. 28, 1986 at p1493 and Mar. 28,1987 at p754 diltiazem given orally at 60 mg was found to reduceinternal anal resting pressure and to treat proctalgia fugax. There was,however, no suggestion of diltiazem being used to treat anal fissure orhaemorrhoids.

[0014] It is an object of the present invention to provide anon-surgical treatment for anal fissures and/or haemorrhoids, or otherbenign anal disorders.

[0015] The inventors have now found that anal fissures and haemorrhoidsand other benign anal disorders can be treated by local application tothe anus of a cholinergic agent or a calcium channel blocker or amixture thereof. Other benign anal disorders would be those conditionsassociated with a high anal pressure or where there is an associatedanal sphincter spasm.

[0016] Accordingly in a first aspect of the invention, there is provideduse of at least one of a cholinergic agent or a calcium channel blockerin the preparation of a medicament for local application to the anus forthe treatment or prophylaxis of benign anal disorders.

[0017] To the inventors knowledge the active agents are usuallyadministerd orally or intraveneously and have never before beencontemplated in topical form. Accordingly, a second aspect of theinvention provides a composition adapted for local application to theanus comprising at least one of a cholinergic agent or a calcium channelblocker together with a pharmaceutically acceptable carrier.

[0018] By local application to the anus we mean to include localinjection into the anal sphincter, and administration in and around theanal canal, preferably by topical application such as spreading atopical composition in and around the anal canal.

[0019] Without being bound by theory, it is believed that thecholinergic agents and calcium channel blockers are at least partiallyeffective (and there may be other mechanisms of action) by lowering theanal resting pressure of the patient. This helps the fissures to heal.This reduction in anal pressure should also allow better venous drainagewhich will allow the haemorroidal vascular cushions to heal.

[0020] In the case of haemorrhoids, it is also thought that thecholinergic agents will act to contract the longitudinal muscle of theanus, thereby pulling the haemorrhoidal cushions back into place.

[0021] In any case the clinical results to date suggest the inventorshave made a major advance in the field by providing a safe andefficacious non-surgical treatment for anal fissures and haemorrhoids.

[0022] By anal fissures we mean to include both acute and chronicfissures or ulcers. Any patient with persistent symptoms for more thantwo weeks is taken to have a chronic fissure in accordance with theinvention.

[0023] By haemorrhoids we mean to include both internal and externalhaemorrhoids and acute thrombosis of external haemorrhoid (TEM).

[0024] Suitable cholinergic agents in accordance with the invention areselected from a cholinergic agonist of acetylcholine, bethanechol,carbachol, methacholine, and pilocarpine, or an anticholinesterase ofambenonium, neostigmine, physostigmine, pyridostigmine, dyflos, andecothinopate, and pharmaceutically acceptable salts of thereof.

[0025] Bethanechol and salts thereof is a particularly preferredcholinergic agent.

[0026] Suitable calcium channel blockers in accordance with theinvention are selected from amlodipine, anipamil, barnidipine,benidipine, bepridil, darodipine, diltiazem, efonidipine, felodipine,isradipine, lacidipine, lercanidipine, lidoflazine, manidipine,mepirodipine, nicardipine, nifedipine, niludipine, nilvadipine,nimodipine, nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil,and pharmaceutically acceptable salts thereof.

[0027] Diltiazem and salts thereof is a particularly preferred calciumchannel blocker.

[0028] A further preferred aspect of the invention provides acomposition for local application to the anus, particularly topicallyacting composition, but not exclusively for topical application in andaround the anal canal comprising diltiazem or bethanechol or acombination thereof or pharmaceutically acceptable salts thereof,together with a pharmaceutically acceptable carrier.

[0029] Accordingly in a preferred aspect of the invention there isprovided the use of diltiazem or bethanechol or a combination thereofand pharmaceutically acceptable salts thereof in the preparation of atopical medicament for the treatment or prophylaxis of benign analdisorders, particularly in the treatment of anal fissures andhaemorrhoids.

[0030] Pharmaceutically acceptable salts of the aforementioned agents,such as of diltiazem and bethanechol, include those formed with bothorganic and inorganic acids. Such acid addition salts will normally bepharmaceutically acceptable although salts of non-pharmaceuticallyacceptable salts may be of utility in the preparation and purificationof the compound in question. Thus, preferred salts include those formedfrom hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric,lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic,methanesulphonic, ethanesulphonic, benzenesulphonic, and isethionicacids. Salts of the compounds of formula (1) can be made by reacting theappropriate compound in the form of the free base with the appropriateacid. Salts of halides are also suitable. Diltiazem hydrochloride,diltiazem malate and diltiazem have CAS registry numbers respectively asfollows: 33286-22-5, 144604-00-2, and 42399-41-7. Bethanechol andbethanechol chloride have CAS registry numbers respectively of 674-38-4and 590-63-6.

[0031] Diltiazem and bethanechol are of great benefit when topicallyadministered separately, but are of particular benefit and apparentlyexhibit a synergistic activity when administered together.

[0032] A suitable proportion of calcium channel blocker, such asdiltiazem in a topical or local composition for a beneficial effect isat least 0.5% w/w, such as 0.5% to 10% w/w, preferably 0.5% to 5% w/w,more preferably still 1% to 5% w/w, still more preferably 1% to 3%, andmost preferably about 2% w/w. Preliminary dose ranging studies suggestthat the maximum effect of the invention is obtained at about 2% andthereafter higher concentrations will not produce a substantialadditional effect.

[0033] The diltiazem composition is suitably applied 3 to 6 times,preferably 3 to 4 times daily, which based on 8 mg per application,gives a total daily dose of 24 mg to 48 mg.

[0034] A suitable proportion of cholinergic agent, such as bethanecholin a topical or local composition is at least 0.01% w/w, more preferablyat least 0.05% such as 0.01% to 3% w/w, preferably 0.01% to 1% w/w, morepreferably 0.05% to 1% w/w, and most preferably about 0.1% w/w.Preliminary dose ranging studies suggest that 0.1% w/w produced themaximum effect of the invention, and thereafter higher concentrationswill not produce an additional effect.

[0035] The bethanechol composition is suitably applied in the sameregimin as above which based on 0.4 mg per application, gives a totaldaily dose of 1.2 mg to 2.4 mg.

[0036] Pharmaceutical compositions adapted for topical administration inand/or around the anal canal may be formulated as ointments, creams,suspensions, lotions, powders, solutions, pastes, gels, sprays, foam,oils, aerosols, suppositories or enemas.

[0037] The topical compositions can comprise emulsifiers, preservatives,buffering agents and anti-oxidants. Preferably the compositions alsocomprise steroids (e.g. present at 0.1 to 5% w/w) such as prednisolone,busenonide or hydrocortisone, locally acting anaesthetics such aslignocaine (e.g. at 0.1 to 5% w/w), and soothants. Typical componentsused in existing fissure or haemorrhoidal treatments which can also beused in topical compositions of the invention include: zinc oxide,benzyl benzoate, bismuth oxide, bismuth subgallate and Peru balsam.

[0038] In accordance with the invention, the cholinergic agent orcalcium channel blocker can be administered in combination withtrinitroglycerine or any other nitric oxide donor, isoprenaline,histamine, prostaglandin E₂, adenosine triphosphate, nictotine, DMPP,bradykinin, caerulein, glucagon, and phentolamine.

[0039] The topical composition may comprise skin penetrating agents,particularly the sulphoxides, such as dimethyl sulphoxide (DMSO)preferably at 25% to 50% w/w. Amides, (DMA, DMF) pyrrolidones, organicsolvents, laurocaprom (AZONE) and calcium thioglycollate are suitablealternative penetrants. The composition may also optionally contains apolyacrylic acid derivative, more particularly a carbomer. This wouldboth act as a skin hydrating agent to aid penetration of the drug, butalso an emulsifying agent. The carbomer will help emulsify the DMSO,thereby mitigating skin irritation and providing enhanced skinhydration. Propylene glycol may also be present in the composition tosoften the skin, increase thermodynamic potential and aid skinpenetration by the DMSO and thus the drug. The final pH of thecomposition is advantageously pH 3.5 to 4.5.

[0040] Further aspects of the invention are as follows:

[0041] A. A method for the treatment or prophylaxis of a benign analdisorder comprising local application to the anus or the internal analsphincter at least one of a cholinergic agent or calcium channelblocker.

[0042] B. An anal fissure and haemorroidal topical compositioncomprising at least one of a cholinergic agent or calcium channelblocker, together with a pharmaceutically acceptable carrier.

[0043] Early investigations suggest that the DMSO cream in the clinicalstudies may also have a therapeutic effect independent of thebethanechol or diltiazem. Thus a yet further aspect of the inventionprovides use of DMSO as a therapeutically active agent in thepreparation of a topical medicament for the treatment of benign analdisorders, particularly anal fissure or haemorrhoids.

[0044] Preferably the DMSO is present at 25% to 50% w/w, and isadvantageously present in combination with propylene glycol, preferablyin a ratio by w/w of 5:1 to 15:1. The DMSO composition of this furtheraspect of the invention is also advantageously present with apolyacrylic acid derivative, such as carbomer, preferably at a ratio byw/w of 20:1 to 80:1. Preferably the pH of the composition is pH 3.5 to4.5.

[0045] The invention will now be described by way of example only withreference to the accompanying drawings, in which:

[0046]FIG. 1 is a graph of the dose response of diltiazem gel againstmean anal resting pressure;

[0047]FIG. 2 is a graph of duration of action of 1% w/w diltiazem gelagainst mean anal resting pressure;

[0048]FIG. 3 is a graph of the dose response of bethanechol gel againstmean anal resting pressure;

[0049]FIG. 4 is a graph of duration of action of 0.1% w/w bethanecholgel against mean anal resting anal pressure; and

[0050]FIG. 5 is a graph comparing 2% diltiazem, 0.1% bethanechol, and acombination of both over time against the reduction in mean anal restingpressure.

EXAMPLE 1

[0051] A composition of base gel had the following composition:carmellose sodium 6 g, polyethylene glycol 30 ml, methylhydroxybenzoate150 mg, propylhydroxybenzoate 15 mg, made up to volume with distilledwater (pH6-7).

[0052] Various amounts of diltiazem and bethanechol were added in theamounts shown in examples 4 and 6 to form various compositions for doseranging studies.

EXAMPLE 2

[0053] A base cream of the invention had the following composition:Diltiazem hydrochloride (2% w/w) 10 g Dimethyl sulphoxide 250 g Carbomer974P 5 g White soft paraffin 15 g Cetomacrogel emulsifying ointment* 115g Propylene glycol 23 g Methylhydroxybenzoate (preservative soln) to 500g

[0054] A base cream was formed by firstly separate mixing of the aqueousand non-aqueous components of the cream. Weighed quantities of propyleneglycol and a proportion of the preservative solution were placed in abeaker to which the weight quantity of carbomer powder was added usingan impeller type mixer to form a colloidal suspension of the carbomer.Thereafter, the weighed quantity of DMSO was added and rapid stirringcontinued at room temperature until a translucent uniform gel had beenformed.

[0055] In the meantime, the weighed quantities of white soft paraffinand the cetamacrogol emulsifying ointment were placed in a separatebeaker, heated to melting point and gently stirred to give a uniformbase.

[0056] The drug is then added to the remainder of the preservativesolution , which in turn was then added to the gel and whilst vigorouslystirring, the uniform base (above) was added to form a cream. Thecarbomer acted as a dual neutralisation agent and primary emulsifier (ofthe oil and aqueous phases) to form the uniform cream base.

EXAMPLE 3

[0057] A bethanechol cream composition was made up as above, but using0.5 g of bethanechol (0.1% w/w) instead of diltiazem.

EXAMPLE 4 Diltiazem Cream and Tablet—Dose Ranging Study on HealthyVolunteers

[0058] Ten volunteers were used in a double blind study to determine theconcentration of diltiazem cream (of example 1) which most effectivelylowers resting anal sphincter pressure as measured by an eight channelwater perfused manometer. Concentrations of diltiazem cream used were0.1%, 0.5%, 1%, 2%, 5% and 10%. Results showed a dose dependentreduction of the resting anal sphincter pressure. The maximal effect, atwhich the mean resting anal pressure was lowered by 28% (P<0.0001), wasproduced by 2% w/w cream (See FIG. 1). Higher concentrations did notproduce an additional effect. A typical ‘one inch’ application of thecream from the tube is equivalent to 8 mg dose of diltiazem.Measurements taken throughout the day showed the effect of a singleapplication to be sustained for 3 to 5 hours (see FIG. 2).

EXAMPLE 5 Open Study of Diltiazem Cream in Patients with Anal Fissures

[0059] 2% diltiazem cream from example 2 was applied to the anus threetimes daily for 8 weeks to treat patients suffering from chronic analfissures (in an uncontrolled, open, pilot study). To date, 7 patientswere studied and followed up between 2 to 5 weeks. 5 patients have hadcomplete resolution of symptoms, of whom 3 have complete and 2 partialhealing of the fissure. In four of these 5 patients there has been areduction of the maximum resting anal sphincter pressure to withinnormal limits. The last patient, though symptom free, continues to havea high anal resting pressure.

[0060] 2 patients have only had two weeks of treatment and one issymptom free after this short period, whilst the other still hasoccasional pain. It is too early to comment on healing of fissures inthese two patients.

EXAMPLE 6 Bethanechol Cream—Dose Ranging Study in Healthy Volunteers

[0061] Ten volunteers were used in a double blind study to determine theconcentration of bethanechol gel which most effectively lowered restinganal sphincter pressure.

[0062] Bethanechol cream at concentrations of 0.05%, 0.1%, 0.5% and 1%w/w bethanechol were made up in accordance with example 1. Thecompositions were studied following initial experimentation in an openway to determine a clinically effective dose range. Results showed adose dependent reduction in the resting anal sphincter pressure (seeFIG. 3). Maximal effect was produced by application of 0.1% bethanecholand higher concentrations of the cream produced no additional effect. At0.1% w/w bethanechol, the mean resting pressure was reduced from about110 cm to about 85 cm H₂O (about 25% decrease). A typical ‘one inch’application of this cream from the tube is equivalent to 400 mcg ofbethanechol. Measurements taken throughout the day showed the effect ofa single application to be sustained from 3 to 5 hours (see FIG. 4).

EXAMPLE 7 Open Study of Bethanechol Cream in Patients with Chronic AnalFissures

[0063] The 0.1% bethanechol cream of example 3 was applied to the anusthree times daily for an eight week course to treat patients sufferingfrom chronic anal fissures (in an uncontrolled, open, pilot study). Todate, 6 patients have been treated and followed up for 3 to 5 weeks.Four patients have had complete resolution of symptoms, of whom 3 havecomplete and 1 partial healing of the fissure. In all of these 4patients there has been a reduction of the maximum resting analsphincter pressure to within normal limits. One patient discovered shewas pregnant and treatment was discontinued. The last patient has had norelief and remains symptomatic after 4 weeks' follow up.

[0064] These results shows that both bethanechol and diltiazem (appliedtopically) reduce the resting anal sphincter pressure in healthy anddiseased patients. The preliminary open studies, albeit in a small groupof patients, has shown a significant healing rate and symptom reliefafter only a few weeks application of both agents. This is a majorachievement for the non-surgical treatment of fissures and offers hopeto its many sufferers.

[0065] When the study of example 4 was repeated using 60 mg oraldiltiazem once a day, no notable effect was obtained. At 60 mg twice aday, the mean anal resting pressure was reduced by 17% (P=0.008), buttwo patients notices postural dizziness. Topical diltiazem issurprisingly safer and more effective than oral diltiazem.

EXAMPLE 8

[0066] In a combined bethanechol and diltiazem study, six healthyvolunteers had topically applied to their anus on different days:

[0067] 1) diltiazem at 2% w/w alone;

[0068] 2) bethanechol at 0.1% w/w alone; and

[0069] 3) diltiazem and bethanechol combined.

[0070] Anal mamometry was carried out before and after each of the threecreams were applied and repeated at two hourly intervals. The meanresults are shown in FIG. 5.

[0071] These show that the combination of diltiazem and bethanecholgives a larger reduction in the mean anal resting pressure than eitherof diltiazem or bethanechol alone. This synergy may be due to bothagents working in different mechanistic pathways to effect the pressuredrop.

[0072] In summary, the results show that local application to the anusof at least one of a cholinergic agent or calcium channel provides aefficacious treatment for benign anal disorder, particularly analfissures and haemorrhoids. Furthermore since efficacy can be obtained atsurprisingly low doses, the treatment of the invention is alsosubstantially free of side effects normally associated with the activeagents.

What is claimed is:
 1. A method of treating an anorectal disorder, andfor controlling the pain associated therewith, the method comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a calcium channel blocker either alone or togetherwith a nitric oxide donor.
 2. A method in accordance with claim 1,wherein both the calcium channel blocker and nitric oxide donor areadministered.
 3. A method in accordance with claim 2, wherein saidnitric oxide donor and said calcium channel blocker are administered incombination.
 4. A method in accordance with claim 1, wherein saidanorectal disorder is an anal fissure.
 5. A method in accordance withany one of claims 1, 2, 3 or 4, wherein said administration is topical.6. A method in accordance with claim 5, wherein said administration isin the form of a gel, ointment, cream, emollient, lotion, powder,solution, suspension, spray, paste, oil, foam, suppository or enema. 7.A method in accordance with claim 6, wherein said calcium channelblocker is administered in an amount within the range of from 0.5% to 5%w/w.
 8. A method of treating a benign anal disorder, the methodcomprising administering to a subject in need of such treatment atherapeutically effective amount of a calcium channel blocker eitheralone or together with a nitric oxide donor.
 9. A method in accordancewith claim 8, wherein both the calcium channel blocker and nitric oxidedonor are administered.
 10. A method in accordance with claim 9, whereinsaid nitric oxide donor and calcium channel blocker are administered incombination.
 11. A method in accordance with claim 8, wherein saidanorectal disorder is an anal fissure.
 12. A method in accordance withany one of claims 8, 9, 10 or 11, wherein said administration istopical.
 13. A method in accordance with claim 12, wherein saidadministration is in the form of a gel, ointment, cream, emollient,lotion, powder, solution, suspension, spray, paste, oil, foam,suppository or enema.
 14. A method in accordance with claim 13, whereinsaid calcium channel blocker is administered in an amount within therange of from 0.5% to 5% w/w.
 15. A method of treating an anorectaldisorder, and for controlling the pain associated therewith, the methodcomprising administering to a subject in need of such treatment atherapeutically effective amount of an agent selected from the groupconsisting of diltiazem, nifedipine and pharmaceutically acceptablesalts thereof either alone or together with a nitric oxide donor.
 16. Amethod in accordance with claim 15, wherein both said agent and thenitric oxide donor are administered.
 17. A method in accordance withclaim 16, wherein said agent and said nitric oxide donor areadministered in combination.
 18. A method in accordance with claim 15,wherein said anorectal disorder is an anal fissure.
 19. A method inaccordance with any one of claims 15, 16, 17 or 18, wherein saidadministration is topical.
 20. A method in accordance with claim 19,wherein said administration is in the form of a gel, ointment, cream,emollient, lotion, powder, solution, suspension, spray, paste, oil,foam, suppository or enema.
 21. A method in accordance with claim 20,wherein said calcium channel blocker is administered in an amount withinthe range of from 0.5% to 5% w/w.
 22. A method of treating a benign analdisorder, the method comprising administering to a subject in need ofsuch treatment a therapeutically effective amount of an agent selectedfrom the group consisting of diltiazem, nifedipine and pharmaceuticallyacceptable salts thereof either alone or together with a nitric oxidedonor.
 23. A method in accordance with claim 22, wherein both said agentand said nitric oxide donor are administered.
 24. A method in accordancewith claim 23, wherein said agent and said nitric oxide donor areadministered in combination.
 25. A method in accordance with claim 22,wherein said anorectal disorder is an anal fissure.
 26. A method inaccordance with any one of claims 22, 23, 24 or 25, wherein saidadministration is topical.
 27. A method in accordance with claim 26,wherein said administration is in the form of a gel, ointment, cream,emollient, lotion, powder, solution, suspension, spray, paste, oil,foam, suppository or enema.
 28. A method in accordance with claim 27,wherein said calcium channel blocker is administered in an amount withinthe range of from 0.5% to 5% w/w.
 29. A method of treating an anorectaldisorder, and for controlling the pain associated therewith, the methodcomprising administering to a subject in need of such treatment atherapeutically effective amount of a composition comprising apharmaceutically acceptable carrier and an agent which increases a levelof cyclic guanidine monophosphate or cyclic adenosine monophosphate in atissue of an anal sphincter muscle of the subject, thereby decreasinghypertonicity of the anal sphincter muscle of the subject, whichcomposition comprises a calcium channel blocker either alone or togetherwith a nitric oxide donor.
 30. A method according to claim 29, whereinboth said calcium channel blocker and said nitric oxide donor areadministered.
 31. A method for the treatment or prophylaxis of benignanal disorders comprising local application to the anus of a patient atherapeutically effective amount of a calcium channel blocker eitheralone or in combination with a nitric oxide donor.
 32. A method inaccordance with claim 31, wherein both said calcium oxide blocker andsaid nitric oxide donor are administered.
 33. A method in accordancewith claim 32, wherein said calcium oxide blocker and said nitric oxidedonor are administered in combination.
 34. A method in accordance withclaim 31, wherein said administration is in the form of a gel, ointment,cream, emollient, lotion, powder, solution, suspension, spray, paste,oil, foam, suppository or enema.
 35. A method in accordance with claim34, wherein said calcium channel blocker is administered in an amountwithin the range of from 0.5% to 5% w/w.
 36. A method for the treatmentor prophylaxis of benign anal disorders associated with high analpressure or anal sphincter spasm, comprising local application to theanus of a patient a therapeutically effective amount of a calciumchannel blocker either alone or in combination with a nitric oxidedonor.
 37. A method in accordance with claim 36, wherein both saidcalcium oxide blocker and said nitric oxide donor are administered. 38.A method in accordance with claim 37, wherein said calcium oxide blockerand said nitric oxide donor are administered in combination.
 39. Amethod in accordance with claim 36, wherein said administration is inthe form of a gel, ointment, cream, emollient, lotion, powder, solution,suspension, spray, paste, oil, foam, suppository or enema.
 40. A methodin accordance with claim 39, wherein said calcium channel blocker isadministered in an amount within the range of from 0.5% to 5% w/w.
 41. Amethod for the treatment or prophylaxis of benign anal disordersassociated with high anal pressure or anal sphincter spasm, and therelief of symptoms associated therewith, comprising local application tothe internal anal sphincter of a patient a therapeutically effectiveamount of a calcium channel blocker either alone or together with anitric oxide donor.
 42. A method in accordance with claim 41, whereinboth said calcium oxide blocker and said nitric oxide donor areadministered.
 43. A method in accordance with claim 42, wherein saidcalcium oxide blocker and said nitric oxide donor are administered incombination.
 44. A method according to any one of claims 1, 8,15, 29,31, 36 or 41, wherein the calcium channel blocker is selected from thegroup consisting of amlodipine, anipamil, barnidipine, benidipine,bepridil, darodipine, diltiazem, efonidipine, felodipine, isradipine,lacidipine, lercanidipine, lidoflazine, manidipine, mepirodipine,nicardipine, nifedipine, niludipine, nilvadipine, nimodipine,nisoldipine, nitrendipine, perhexiline, tiapamil, verapamil, andpharmaceutically acceptable salts thereof.
 45. A method according to anyone of claims 1, 8, 15, 22, 29, 31, 36 or 41, wherein the nitric oxidedonor is trinitroglycerine.
 46. A method according to any one of claims1, 8, 15, 22, 29, 31, 36 or 41, wherein the anal disorder ishemorrhoids.
 47. A method in accordance with claim 41, wherein saidadministration is in the form of a gel, ointment, cream, emollient,lotion, powder, solution, suspension, spray, paste, oil, foam,suppository or enema.
 48. A method in accordance with claim 47, whereinsaid calcium channel blocker is administered in an amount within therange of from 0.5% to 5% w/w.
 49. A composition adapted for topicalapplication in and around the anal canal comprising a calcium channelblocker and a nitric oxide donor together with a pharmaceuticallyacceptable carrier.
 50. A composition according to claim 49, wherein thecalcium channel blocker is selected from the group consisting ofamlodipine, anipamil, barnidipine, benidipine, bepridil, darodipine,diltiazem, efonidipine, felodipine, isradipine, lacidipine,lercanidipine, lidoflazine, manidipine, mepirodipine, nicardipine,nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, perhexiline, tiapamil, verapamil, and pharmaceuticallyacceptable salts thereof.
 51. A composition according to claim 50,wherein the calcium channel blocker is selected from the groupconsisting of diltiazem, nifedipine and pharmaceutically acceptablesalts thereof.
 52. A composition according to claim 49, wherein thenitric oxide donor is trinitroglycerine or a pharmaceutically acceptablesalt thereof.
 53. A composition according to claim 51, wherein saidcalcium channel blocker is diltiazem.
 54. A method in accordance withclaim 49, wherein said composition is in the form of a gel, ointment,cream, emollient, lotion, powder, solution, suspension, spray, paste,oil, foam, suppository or enema.
 55. A method in accordance with claim49, wherein said calcium channel blocker is present in an amount withinthe range of from 0.5% to 5% w/w.